Method for deuteration of a heterocyclic ring

ABSTRACT

The present invention relates to a method for deuteration of a heterocyclic ring, which comprises subjecting a compound having a heterocyclic ring to sealed refluxing state in a deuterated solvent in the presence of an activated catalyst selected form a palladium catalyst, a platinum catalyst, a rhodium catalyst, a ruthenium catalyst, a nickel catalyst and a cobalt catalyst. In accordance with a method of the present invention, a hydrogen atom belonging to a heterocyclic ring of a compound having a heterocyclic ring can be very efficiently deuterated because temperature of deuteration reaction can be maintained at higher than boiling point of the solvent. 
     Further, a method for deuteration of the present invention can be applied widely to deuteration of various compounds having a heterocyclic ring which are liable to decomposition under supercritical conditions or acidic conditions, leading to industrial and efficient deuteration of a compound having a heterocyclic ring.

TECHNICAL FIELD

The present invention relates to a method for deuteration of aheterocyclic ring, using an activated catalyst.

BACKGROUND OF THE INVENTION

A compound having a heavy hydrogen (deuterium and tritium) is said to beuseful in various purposes. For example, a deuterated compound is veryuseful in elucidation of reaction mechanism and substance metabolism andused widely as a labeled compound. Said compound is also known to beuseful as drugs, pesticides, organic EL materials, and the like due tochange in stability and property itself by isotope effect thereof. Acompound having tritium also is said to be useful as a labeled compoundin animal tests and the like to survey absorption, distribution,concentration in blood, excretion, metabolism and the like of drugs,etc. Therefore, research on a compound having a heavy hydrogen(deuterium and tritium) has been increasing also in these fields.

Various methods for obtaining these compounds having a heavy hydrogenhave conventionally been used, however, among others, there are manyproblems to be solved in deuteration technology of a heterocyclic ring,and it was difficult to efficiently and industrially obtain a compoundhaving a deuterated heterocyclic ring.

Conventional technology includes, for example, a method for deuterationof a compound having a heterocyclic ring using heavy water, deuteratedhydrochloric acid and mercaptoacetic acid [Tetrahedron Letters, 43(2002), 2389-2392], a method for deuteration of a compound having aheterocyclic ring under a supercritical condition using supercriticalheavy water and deuterated anion (Chemical Society Reviews, 1997, Volume26, 401-406), and a method for deuteration of a compound having aheterocyclic ring at 100° C. using a palladium catalyst reduced withhydrogen gas in advance (Chem. Commun., 2001, 367-368).

However, a method containing the addition process of an acid to areaction system is not only impossible to deuterate a compound having aheterocyclic ring labile to decomposition under acidic condition butalso has a problem that a complicated purifying procedure is required toisolate a deuterated compound by said method because the reaction liquidis not neutral, even if a compound which does not decompose in acidiccondition is used as a substrate.

Further, a method using supercritical heavy water has problems that acompound to be a reaction substrate tends to be easily decomposed due tovery high reactivity of the supercritical water, as well as that thereaction itself must be conducted under a severe condition such assupercritical condition.

Furthermore, a method wherein the deuteration reaction is conducted at100° C. using a palladium catalyst reduced with hydrogen gas in advanceand heavy water requires a complicated procedure that the palladiumcatalyst reduced with hydrogen gas has to be freeze-pumped repeatedlybefore use for the deuteration reaction.

In view of the above situation, development of a method is needed fordeuteration of a compound having a heterocyclic ring efficiently andindustrially irrespective of presence and non-presence of a substituentor types thereof.

SUMMARY OF THE INVENTION

The present invention relates to a method for deuteration of aheterocyclic ring, characterized by subjecting a compound having aheterocyclic ring to sealed refluxing state in a deuterated solvent inthe presence of an activated catalyst selected from a palladiumcatalyst, a platinum catalyst, a rhodium catalyst, a ruthenium catalyst,a nickel catalyst and a cobalt catalyst.

BEST MODE FOR CARRYING OUT OF THE INVENTION

In the present invention, heavy hydrogen means deuterium (D) and tritium(T) and deuteration means substitution with deuterium and tritium.Further, in the present specification, deuteration ratio means ratio ofamount of hydrogen atom substituted by a deuterium or a tritium atom toamount of hydrogen atom in a compound having a heterocyclic ring.

In a method for deuteration of the present invention, a compound havinga heterocyclic ring includes a compound having a heterocyclic ringcontaining not less than 1 hetero atom, preferably 1 to 3 hetero atomsand not less than 1 hydrogen atom present on said heterocyclic ring.

The hetero atom contained in a heterocyclic ring includes generally anitrogen atom, an oxygen atom, a sulfur atom and the like, and amongothers, a nitrogen atom is preferable.

The heterocyclic ring as described above includes generally 3- to20-membered, preferably 3- to 14-membered, more preferably 5- to10-membered monocyclic heterocyclic ring or polycyclic heterocyclicring, which may have aromatic properties. Further, the heterocyclic ringis, in the case of a monocyclic heterocyclic ring, still more preferably5- to 6-membered, and in the case of a polycyclic heterocyclic ring,still more preferably 9- to 10-membered and particularly preferably9-membered. These heterocyclic rings may be condensed in straightchained state, branched state or cyclic state and may take planestructure or stereo structure.

Further, said heterocyclic ring may have generally 1 to 5, preferably 1to 2, more preferably 1 substituent.

Specific examples of the monocyclic heterocyclic ring include, forexample, 3-membered heterocyclic rings having one hetero atom such asoxirane ring and aziridine ring; 5-membered heterocyclic rings havingone hetero atom such as furan ring, thiophene ring, pyrrole ring,2H-pyrrole ring, pyrroline ring, 2-pyrroline ring and pyrrolidine ring;5-membered heterocyclic rings having two hetero atoms such as1,3-dioxolan ring, oxazole ring, isooxazole ring, 1,3-oxazole ring,thiazole ring, isothiazole ring, 1,3-thiazole ring, imidazole ring,imidazoline ring, 2-imidazoline ring, imidazolidine ring, pyrazole ring,pyrazoline ring, 3-pyrazoline ring and pyrazolidine ring; 5-memberedheterocyclic rings having three hetero atoms such as furazan ring,triazole ring, thiadiazole ring and oxadiazole ring; 6-memberedheterocyclic rings having one hetero atom such as pyran ring, 2H-pyranring, pyridine ring and piperidine ring; 6-membered heterocyclic ringshaving two hetero atoms such as thiopyrane ring, pyridazine ring,pyrimidine ring, pyrazine ring, piperazine ring and morpholine ring;6-membered heterocyclic rings having three hetero atoms such as1,2,4-triazine ring.

The polycyclic heterocyclic ring includes one wherein 2 to 3 monocyclicheterocyclic rings are condensed each other, or a bicyclic heterocyclicring or a tricyclic heterocyclic ring, wherein a monocyclic heterocyclicring is condensed with 1 to 2 aromatic rings such as a benzene ring anda naphthalene ring.

Specific examples of the bicyclic heterocyclic ring include, forexample, heterocyclic rings having one hetero atom such as benzofuranring, isobenzofuran ring, 1-benzothiophene ring, 2-benzothiophene ring,indole ring, 3-indole ring, isoindole ring, indolizine ring, indolinering, isoindoline ring, 2H-chromene ring, chroman ring, isochroman ring,1H-2-benzopyran ring, quinoline ring, isoquinoline ring and4H-quinolizine ring; heterocyclic rings having two hetero atoms such asbenzoimidazole ring, benzothiazole ring, 1H-indazole ring,1,8-naphthyridine ring, quinoxaline ring, quinazoline ring,quinazolidine ring, cinnoline ring and phthalazine ring; heterocyclicrings having four hetero atoms such as purine ring and pteridine ring.

Specific examples of the tricyclic heterocyclic ring include, forexample, heterocyclic rings having one hetero atom such as carbazolering, 4aH-carbazole ring, xanthene ring, phenanthridine ring andacridine ring; heterocyclic rings having two hetero atoms such asβ-carboline ring, perimidine ring, 1,7-phenanthroline ring,1,10-phenanthroline ring, thianthrene ring, phenoxathiin ring,phenoxazine ring, phenothiazine ring and phenazine ring.

Specific examples of the substituent of the above heterocyclic ringwhich may have a substituent include, for example, a halogen atom, ahydroxyl group, a mercapto group, an oxo group, a thioxo group, acarboxyl group, a sulfo group, a sulfino group, a sulfeno group, aphosphino group, a phosphinoyl group, a formyl group, an amino group, acyano group and a nitro group, and moreover an alkyl group, an alkenylgroup, an aryl group, an aralkyl group, an alkoxy group, an aryloxygroup, an alkylthio group, an arylthio group, an alkylsulfonyl group, anarylsulfonyl group, an alkylsulfinyl group, an arylsulfinyl group, analkylphosphino group, an arylphosphino group, an alkylphosphinoyl group,an arylphosphinoyl group, an alkylamino group, an arylamino group, analkoxycarbonyl group, an aryloxycarbonyl group, an alkoxysulfonyl group,an aryloxysulfonyl group, an acyl group and an acyloxy group, which mayfurther have a substituent.

The above alkyl group may be straight chained, branched or cyclic, andincludes one generally having 1 to 20, preferably 1 to 15, morepreferably 1 to 10 and further preferably 1 to 6 carbon atoms, which isspecifically exemplified by a methyl group, an ethyl group, a n-propylgroup, an isopropyl group, a n-butyl group, an isobutyl group, asec-butyl group, a tert-butyl group, a n-pentyl group, an isopentylgroup, a sec-pentyl group, a tert-pentyl group, a neopentyl group, an-hexyl group, an isohexyl group, a 3-methylpentyl group, a2-methylpentyl group, a 1,2-dimethylbutyl group, a n-heptyl group, anisoheptyl group, a sec-heptyl group, an n-octyl group, an isooctylgroup, a sec-octyl group, a n-nonyl group, a n-decyl group, an n-undecylgroup, a n-dodecyl group, a n-tridecyl group, a n-tetradecyl group, an-pentadecyl group, a n-hexadecyl group, a n-heptadecyl group, ann-octadecyl group, a n-nonadecyl group, an n-icosyl group, a cyclopropylgroup, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, acyclooctyl group, a cyclononyl group, a cyclodecyl group, a cycloundecylgroup, a cyclododecyl group, a cyclotridecyl group, a cyclotetradecylgroup, a cyclopentadecyl group, a cyclohexadecyl group, acycloheptadecyl group, a cyclooctadecyl group, a cyclononadecyl groupand a cycloicosyl group.

The alkenyl group may be straight chained, branched or cyclic, andincludes one generally having 2 to 20, preferably 2 to 10 and morepreferably 2 to 6 carbon atoms, and having not less than 1 carbon-carbondouble bond in the chain of the above alkyl group having not less than 2carbon atoms, among the above alkyl groups, which is specificallyexemplified by a vinyl group, an allyl group, a 1-propenyl group, anisopropenyl group, a 3-butenyl group, a 2-butenyl group, a 1-butenylgroup, a 1,3-butadienyl group, a 4-pentenyl group, a 3-pentenyl group, a2-pentenyl group, a 1-pentenyl group, a 1,3-pentadienyl group, a2,4-pentadienyl group, a 1,1-dimethyl-2-propenyl group, an1-ethyl-2-propenyl group, a 1,2-dimethyl-1-propenyl group, a1-methyl-1-butenyl group, a 5-hexenyl group, a 4-hexenyl group, a2-hexenyl group, a 1-hexenyl group, a 1-methyl-1-hexenyl group, a2-methyl-2-hexenyl group, a 3-methyl-1,3-hexadienyl group, a 1-heptenylgroup, an 2-octenyl group, a 3-nonenyl group, a 4-decenyl group, a1-dodecenyl group, a 1-tetradecenyl group, a 1-hexadecenyl group, an1-octadecenyl group, a 1-icosenyl group, a 1-cyclopropenyl group, a2-cyclopentenyl group, a 2,4-cyclopentadienyl group, a 1-cyclohexenylgroup, a 2-cyclohexenyl group, a 3-cyclohexenyl group, a 2-cycloheptenylgroup, a 2-cyclononenyl group, a 3-cyclodecenyl group, a2-cyclotridecenyl group, a 1-cyclohexadecenyl group, a1-cyclooctadecenyl group and a 1-cycloicosenyl group.

The aryl group includes one generally having 6 to 14, preferably 6 to 10carbon atoms, which is specifically exemplified by a phenyl group, anaphthyl group and an anthryl group.

The aralkyl group may be straight chained, branched or cyclic, andincludes one generally having 7 to 34, preferably 7 to 20 and morepreferably 7 to 15 carbon atoms, which is the above alkyl groupsubstituted with the above aryl group, which is specifically exemplifiedby a benzyl group, a phenylethyl group, a phenylpropyl group, aphenylbutyl group, a phenylpentyl group, a phenylhexyl group, aphenylheptyl group, a phenyloctyl group, a phenylnonyl group, aphenyldecyl group, a phenylundecyl group, a phenyldodecyl group, aphenyltridecyl group, a phenyltetradecyl group, a phenylpentadecylgroup, a phenylhexadecyl group, a phenylheptadecyl group, aphenyloctadecyl group, a phenylnonadecyl group, a phenylicosyl group, anaphthylethyl group, a naphthylpropyl group, a naphthylbutyl group, anaphthylpentyl group, a naphthylhexyl group, a naphthylheptyl group, anaphthyloctyl group, a naphthylnonyl group, a naphthyldecyl group, anaphthylundecyl group, a naphthyldodecyl group, a naphthyltridecylgroup, a naphthyltetradecyl group, a naphthylpentadecyl group, anaphthylhexadecyl group, a naphthylheptadecyl group, a naphthyloctadecylgroup, a naphthylnonadecyl group, a naphthylicosyl group, ananthrylethyl group, an anthrylpropyl group, an anthrylbutyl group, ananthrylpentyl group, an anthrylhexyl group, an anthrylheptyl group, ananthryloctyl group, an anthrylnonyl group, an anthryldecyl group, ananthrylundecyl group, an anthryldodecyl group, an anthryltridecyl group,an anthryltetradecyl group, an anthrylpentadecyl group, ananthrylhexadecyl group, an anthrylheptadecyl group, an anthryloctadecylgroup, an anthrylnonadecyl group, an anthrylicosyl group, aphenanthrylethyl group, a phenanthrylpropyl group, a phenanthrylbutylgroup, a phenanthrylpentyl group, a phenanthrylhexyl group, aphenanthrylheptyl group, a phenanthryloctyl group, a phenanthrylnonylgroup, a phenanthryldecyl group, a phenanthrylundecyl group, aphenanthryldodecyl group, a phenanthryltridecyl group, aphenanthryltetradecyl group, a phenanthrylpentadecyl group, aphenanthrylhexadecyl group, a phenanthrylheptadecyl group, aphenanthryloctadecyl group, a phenanthrylnonadecyl group and aphenanthrylicosyl group.

The alkoxy group may be straight chained, branched or cyclic, andincludes one generally having 1 to 20, preferably 1 to 15, morepreferably 1 to 10 and further preferably 1 to 6 carbon atoms, which isspecifically exemplified by a methoxy group, an ethoxy group, a propoxygroup, an isopropoxy group, a butoxy group, an isobutoxy group, asec-butoxy group, a tert-butoxy group, a pentyloxy group, a neopentyloxygroup, a hexyloxy group, an isohexyloxy group, a tert-hexyloxy group, aheptyloxy group, an octyloxy group, a nonyloxy group, a decyloxy group,an undecyloxy group, a tetradecyloxy group, a hexadecyloxy group, aheptadecyloxy group, a nonadecyloxy group, an icosyloxy group, acyclohexyloxy group, a cyclooctyloxy group, a cyclodecyloxy group and acyclononadecyloxy group.

The aryloxy group includes one generally having 6 to 14, preferably 6 to10 carbon atoms, which is specifically exemplified by a phenoxy group, anaphthyloxy group and an anthryloxy group.

The alkylthio group may be straight chained, branched or cyclic, andincludes one generally having 1 to 20, preferably 1 to 15, morepreferably 1 to 10 and further preferably 1 to 6 carbon atoms, whereinan oxygen atom in the above alkoxy group is replaced by a sulfur atom,which is specifically exemplified by a methylthio group, an ethylthiogroup, a propylthio group, an isopropylthio group, a butylthio group, anisobutylthio group, a tert-butylthio group, a pentylthio group, ahexylthio group, an octylthio group, a nonylthio group, a decylthiogroup, a tridecylthio group, a tetradecylthio group, a hexadecylthiogroup, an octadecylthio group, an icosylthio group, a cyclohexylthiogroup, a cyclodecylthio group and a cycloheptadecylthio group.

The arylthio group includes one wherein an alkyl group in the abovealkylthio group is replaced by the above aryl group, which isspecifically exemplified by a phenylthio group, a naphthylthio group andan anthrylthio group.

The alkylsulfonyl group may be straight chained, branched or cyclic, andincludes one generally having 1 to 20, preferably 1 to 15, morepreferably 1 to 10 and further preferably 1 to 6 carbon atoms, which isspecifically exemplified by a methylsulfonyl group, an ethylsulfonylgroup, a n-propylsulfonyl group, an isopropylsulfonyl group, an-butylsulfonyl group, an isobutylsulfonyl group, a tert-butylsulfonylgroup, a pentylsulfonyl group, a neopentylsulfonyl group, ahexylsulfonyl group, an isohexylsulfonyl group, a tert-hexylsulfonylgroup, a heptylsulfonyl group, an octylsulfonyl group, a nonylsulfonylgroup, a decylsulfonyl group, an undecylsulfonyl group, atetradecylsulfonyl group, a hexadecylsulfonyl group, aheptadecylsulfonyl group, a nonadecylsulfonyl group, an icosylsulfonylgroup, a cyclohexylsulfonyl group, a cyclooctylsulfonyl group, acyclodecylsulfonyl group and a cyclononadecylsulfonyl group.

The arylsulfonyl group includes one generally having 6 to 14, preferably6 to 10 carbon atoms, which is specifically exemplified by aphenylsulfonyl group, a naphthylsulfonyl group and an anthrylsulfonylgroup.

The alkylsulfinyl group may be straight chained, branched or cyclic, andincludes one generally having 1 to 20, preferably 1 to 15, morepreferably 1 to 10 and further preferably 1 to 6 carbon atoms, which isspecifically exemplified by a methylsulfinyl group, an ethylsulfinylgroup, a n-propylsulfinyl group, an isopropylsulfinyl group, an-butylsulfinyl group, an isobutylsulfinyl group, a tert-butylsulfinylgroup, a pentylsulfinyl group, a neopentylsulfinyl group, ahexylsulfinyl group, an isohexylsulfinyl group, a tert-hexylsulfinylgroup, a heptylsulfinyl group, an octylsulfinyl group, a nonylsulfinylgroup, a decylsulfinyl group, an undecylsulfinyl group, atetradecylsulfinyl group, a hexadecylsulfinyl group, aheptadecylsulfinyl group, a nonadecylsulfinyl group, an icosylsulfinylgroup, a cyclohexylsulfinyl group, a cyclooctylsulfinyl group, acyclodecylsulfinyl group and a cyclononadecylsulfinyl group.

The arylsulfinyl group includes one, wherein the alkyl group in theabove alkylsulfinyl group is replaced by the above aryl group, which isspecifically exemplified by a phenylsulfinyl group, a naphthylsulfinylgroup and an anthrylsulfinyl group.

The alkylphosphino group includes one, wherein one or two of hydrogenatoms of a phosphino group is each independently replaced by the abovealkyl group, which is specifically exemplified by a methylphosphinogroup, an ethylphosphino group, a n-propylphosphino group, anisopropylphosphino group, a n-butylphosphino group, an isobutylphosphinogroup, a tert-butylphosphino group, a pentylphosphino group, ahexylphosphino group, a heptylphosphino group, an octylphosphino group,a nonylphosphino group, a decylphosphino group, a dodecylphosphinogroup, a tetradecylphosphino group, a pentadecylphosphino group, ahexadecylphosphino group, a heptadecylphosphino group, anonadecylphosphino group, an icosylphosphino group, acyclopentylphosphino group, a cyclohexylphosphino group, acycloheptylphosphino group, a dimethylphosphino group, anethylmethylphosphino group, a diethylphosphino group, amethylpropylphosphino group, a dipropylphosphino group, anethylhexylphosphino group, a dibutylphosphino group, aheptylmethylphosphino group, a methyloctylphosphino group, adecylmethylphosphino group, a dodecylethylphosphino group, amethylpentadecylphosphino group, an ethyloctadecylphosphino group, acyclopentylmethylphosphino group, a cyclohexylmethylphosphino group, acyclohexylethylphosphino group, a cyclohexylpropylphosphino group, acyclohexylbutylphosphino group and a dicyclohexylphosphino group.

The arylphosphino group includes one, wherein one or two of hydrogenatoms of a phosphino group is each independently replaced by the abovearyl group, which is specifically exemplified by a phenylphosphinogroup, a diphenylphosphino group, a naphthylphosphino group and ananthrylphosphino group.

The alkylphosphinoyl group includes one, wherein one or two of hydrogenatoms of a phosphinoyl group is each independently replaced by the abovealkyl group, which is specifically exemplified by a methylphosphinoylgroup, an ethylphosphinoyl group, a n-propylphosphinoyl group, anisopropylphosphinoyl group, a n-butylphosphinoyl group, anisobutylphosphinoyl group, a tert-butylphosphinoyl group, apentylphosphinoyl group, a hexylphosphinoyl group, a heptylphosphinoylgroup, an octylphosphinoyl group, a nonylphosphinoyl group, adecylphosphinoyl group, a dodecylphosphinoyl group, atetradecylphosphinoyl group, a pentadecylphosphinoyl group, ahexadecylphosphinoyl group, a heptadecylphosphinoyl group, anonadecylphosphinoyl group, a icosylphosphinoyl group, acyclopentylphosphinoyl group, a cyclohexylphosphinoyl group, acycloheptylphosphinoyl group, a dimethylphosphinoyl group, anethylmethylphosphinoyl group, a diethylphosphinoyl group, amethylpropylphosphinoyl group, a dipropylphosphinoyl group, anethylhexylphosphinoyl group, a dibutylphosphinoyl group, aheptylmethylphosphinoyl group, a methyloctylphosphinoyl group, adecylmethylphosphinoyl group, a dodecylethylphosphinoyl group, amethylpentadecylphosphinoyl group, an ethyloctadecylphosphinoyl group, acyclopentylmethylphosphinoyl group, a cyclohexylmethylphosphinoyl group,a cyclohexylethylphosphinoyl group, a cyclohexylpropylphosphinoyl group,a cyclohexylbutylphosphinoyl group and a dicyclohexylphosphinoyl group.

The arylphosphinoyl group includes one, wherein one or two of hydrogenatoms of a phosphinoyl group is replaced by the above aryl group, whichis specifically exemplified by a phenylphosphinoyl group, adiphenylphosphinoyl group, a naphthylphosphinoyl group and ananthrylphophinoyl group.

The alkylamino group includes one, wherein one or two of hydrogen atomsof an amino group is each independently replaced by the above alkylgroup, which is specifically exemplified by a methylamino group, anethylamino group, a n-propylamino group, an isopropylamino group, an-butylamino group, an isobutylamino group, a tert-butylamino group, apentylamino group, a hexylamino group, a heptylamino group, anoctylamino group, a nonylamino group, a decylamino group, a dodecylaminogroup, a tetradecylamino group, a pentadecylamino group, ahexadecylamino group, a heptadecylamino group, a nonadecylamino group,an icosylamino group, a cyclopentylamino group, a cyclohexylamino group,a cycloheptylamino group, a dimethylamino group, an ethylmethylaminogroup, a diethylamino group, a methylpropylamino group, a dipropylaminogroup, an ethylhexylamino group, a dibutylamino group, aheptylmethylamino group, a methyloctylamino group, a decylmethylaminogroup, a dodecylethylamino group, a methylpentadecylamino group, anethyloctadecylamino group, a cyclopentylmethylamino group, acyclohexylmethylamino group, a cyclohexylethylamino group, acyclohexylpropylamino group, a cyclohexylbutylamino group and adicyclohexylamino group.

The arylamino group includes one, wherein one or two of hydrogen atomsof an amino group is replaced by the above aryl group, which isspecifically exemplified by a phenylamino group, a diphenylamino group,a naphthylamino group and an anthrylamino group.

The alkoxycarbonyl group may be straight chained, branched or cyclic,and includes one generally having 2 to 21, preferably 2 to 15, morepreferably 2 to 10 and further preferably 2 to 6 carbon atoms, andhaving further a carbonyl group bonded to an oxygen atom of the abovealkoxy group, which is specifically exemplified by a methoxycarbonylgroup, an ethoxycarbonyl group, a n-propoxycarbonyl group, an-butoxycarbonyl group, a tert-butoxycarbonyl group, a pentyloxycarbonylgroup, a sec-pentyloxycarbonyl group, a neopentyloxycarbonyl group, ahexyloxycarbonyl group, a cyclohexyloxycarbonyl group, aheptyloxycarbonyl group, a cycloheptyloxycarbonyl group, anoctyloxycarbonyl group, a nonyloxycarbonyl group, a decyloxycarbonylgroup, a cyclodecyloxycarbonyl group, an undecyloxycarbonyl group, atetradecyloxycarbonyl group, a heptadecyloxycarbonyl group, anonadecyloxycarbonyl group, an icosyloxycarbonyl group, acyclopentyloxycarbonyl group, a cyclohexyloxycarbonyl group, acyclooctyloxycarbonyl group and a cycloheptadecyloxycarbonyl group.

The aryloxycarbonyl group includes one generally having 7 to 15,preferably 7 to 11 carbon atoms, which is specifically exemplified by aphenyloxycarbonyl group, a naphthyloxycarbonyl group and ananthryloxycarbonyl group.

The alkoxysulfonyl group may be straight chained, branched or cyclic,and includes one generally having 2 to 21, preferably 2 to 15, morepreferably 2 to 10 and further preferably 2 to 6 carbon atoms, havingfurther a sulfonyl group bonded to an oxygen atom of the above alkoxygroup, which is specifically exemplified by a methoxysulfonyl group, anethoxysulfonyl group, a n-propoxysulfonyl group, a n-butoxysulfonylgroup, a tert-butoxysulfonyl group, a pentyloxysulfonyl group, asec-pentyloxysulfonyl group, a neopentyloxysulfonyl group, ahexyloxysulfonyl group, a cyclohexyloxysulfonyl group, aheptyloxysulfonyl group, a cycloheptyloxysulfonyl group, anoctyloxysulfonyl group, a nonyloxysulfonyl group, a decyloxysulfonylgroup, a cyclodecyloxysulfonyl group, an undecyloxysulfonyl group, atetradecyloxysulfonyl group, a heptadecyloxysulfonyl group, anonadecyloxysulfonyl group, an icosyloxysulfonyl group, acyclopentyloxysulfonyl group, a cyclohexyloxysulfonyl group, acyclooctyloxysulfonyl group and a cycloheptadecyloxysulfonyl group.

The aryloxysulfonyl group includes one generally having 7 to 15,preferably 7 to 11 carbon atoms, which is specifically exemplified by aphenyloxysulfonyl group, a naphthyloxysulfonyl group and ananthryloxysulfonyl group.

The acyl group includes one derived from a carboxylic acid or a sulfonicacid, and the acyl group derived from a carboxylic acid includes onederived from an aliphatic carboxylic acid or an aromatic carboxylicacid. The acyl group derived from a sulfonic acid includes one derivedfrom an aliphatic sulfonic acid or an aromatic sulfonic acid.

The acyl group derived from an aliphatic carboxylic acid may be straightchained, branched or cyclic, and may also have a double bond in thechain, and includes one generally having 2 to 20, preferably 2 to 15,more preferably 2 to 10 and further preferably 2 to 6 carbon atoms,which is specifically exemplified by an acetyl group, a propionyl group,a butyryl group, an isobutyryl group, a valeryl group, an isovalerylgroup, a pivaloyl group, a hexanoyl group, a heptanoyl group, anoctanoyl group, a decanoyl group, a lauroyl group, a myristoyl group, apalmitoyl group, a stearoyl group, an icosanoyl group, an acryloylgroup, a methacryloyl group, a crotonoyl group and an oleoyl group. Theacyl group derived from an aromatic carboxylic acid includes onegenerally having 7 to 15, preferably 7 to 11 carbon atoms, which isspecifically exemplified by a benzoyl group, a naphthoyl group and ananthroyl group.

The acyl group derived from an aliphatic sulfonic acid may be straightchained, branched or cyclic, and includes one generally having 1 to 20,preferably 1 to 15, more preferably 1 to 10 and further preferably 1 to6 carbon atoms, which is specifically exemplified by a methylsulfonylgroup, an ethylsulfonyl group, a n-propylsulfonyl group, anisopropylsulfonyl group, a n-butylsulfonyl group, an isobutylsulfonylgroup, a tert-butylsulfonyl group, a n-pentylsulfonyl group, an-hexylsulfonyl group, a heptylsulfonyl group, an octylsulfonyl group, adecylsulfonyl group, a tridecylsulfonyl group, a hexadecylsulfonylgroup, an icosylsulfonyl group, a cyclohexylsulfonyl group and acyclodecylsulfonyl group. The acyl group derived from an aromaticsulfonic acid includes one generally having 6 to 14, preferably 6 to 10carbon atoms, which is specifically exemplified by a phenylsulfonylgroup, a naphthylsulfonyl group and an anthrylsulfonyl group.

The acyloxy group includes an acyloxy group derived from a carboxylicacid having an —O— bonded to the acyl group derived from the abovecarboxylic acid, and the acyloxy group derived from a sulfonic acidhaving an —O— bonded to the acyl group derived from the above sulfonicacid. The acyloxy group derived from the carboxylic acid includes anacyloxy group derived from an aliphatic carboxylic acid and an aromaticcarboxylic acid. The acyloxy group derived from the sulfonic acidincludes an acyloxy group derived from an aliphatic sulfonic acid and anaromatic sulfonic acid.

The acyloxy group derived from the aliphatic carboxylic acid may bestraight chained, branched or cyclic and may have further a double bondin the chain, and includes one generally having 2 to 20, preferably 2 to15, more preferably 2 to 10 and further preferably 2 to 6 carbon atoms,which is specifically exemplified by an acetyloxy group, a propionyloxygroup, a butyryloxy group, an isobutyryloxy group, a valeryloxy group,an isovaleryloxy group, a pivaloyloxy group, a hexanoyloxy group, aheptanoyloxy group, an octanoyloxy group, a decanoyloxy group, alauroyloxy group, a myristoyloxy group, a palmitoyloxy group, astearoyloxy group, an icosanoyloxy group, an acryloyloxy group, amethacryloyl group, a crotonoyl group, an oleoyloxy group, acyclohexanoyloxy group and a cyclodecanoyloxy group. The acyloxy groupderived from the aromatic carboxylic acid includes one generally having7 to 15, preferably 7 to 11 carbon atoms, which is specificallyexemplified by a benzoyloxy group, a naphthoyloxy group and ananthroyloxy group.

The acyloxy group derived from the aliphatic sulfonic acid may bestraight chained, branched or cyclic, and includes one generally having1 to 20, preferably 1 to 15, more preferably 1 to 10 and furtherpreferably 1 to 6 carbon atoms, which is specifically exemplified by amethylsulfonyloxy group, an ethylsulfonyloxy group, an-propylsulfonyloxy group, an isopropylsulfonyloxy group, an-butylsulfonyloxy group, an isobutylsulfonyloxy group, atert-butylsulfonyloxy group, a n-pentylsulfonyloxy group, an-hexylsulfonyloxy group, a heptylsulfonyloxy group, an octylsulfonyloxygroup, a decylsulfonyloxy group, a tridecylsulfonyloxy group, ahexadecylsulfonyloxy group, an icosylsulfonyloxy group, acyclopentylsulfonyloxy group and a cyclohexylsulfonyloxy group. Theacyloxy group derived from the aromatic sulfonic acid includes onegenerally having 6 to 14, preferably 6 to 10 carbon atoms, which isspecifically exemplified by a phenylsulfonyloxy group, anaphthylsulfonyloxy group and an anthrylsulfonyl group.

The halogen atom includes a chlorine atom, a bromine atom, a fluorineatom and an iodine atom, and among others, a chlorine atom ispreferable.

The carboxyl group, the sulfo group, the sulfino group, the sulfenogroup, the phosphino group and the phosphinoyl group include also one,wherein a hydrogen atom in these groups is replaced by an alkali metalatom such as sodium, potassium and lithium.

Among the above substituents of the heterocyclic ring, deuteration of acompound having a substituent such as an alkoxycarbonyl group, anaryloxycarbonyl group and a cyano group, which is labile todecomposition under acidic condition, in accordance with the method ofthe present invention, does not decompose these substituents.

The substituent of a heterocyclic ring which may have a substituent,that is the above alkyl group, alkenyl group, aryl group, aralkyl group,alkoxy group, aryloxy group, alkylthio group, arylthio group,alkylsulfonyl group, arylsulfonyl group, alkylsulfinyl group,arylsulfinyl group, alkylphosphino group, arylphosphino group,alkylphosphinoyl group, arylphosphinoyl group, alkylamino group,arylamino group, alkoxycarbonyl group, aryloxycarbonyl group,alkoxysulfonyl group, aryloxysulfonyl group, acyl group and acyloxygroup, may further have a substituent including, for example, an alkylgroup, an alkenyl group, an alkynyl group, an aryl group, a hydroxygroup, an alkoxy group, an amino group, an alkylamino group, a mercaptogroup, an alkylthio group, an formyl group, an acyl group, a carboxylgroup, an alkoxycarbonyl group, a carbamoyl group and an alkylcarbamoylgroup, and these substituents may be present in number of generally 1 to6, preferably 1 to 4, more preferably 1 to 2 in the substituent of theheterocyclic ring.

The substituent of a heterocyclic ring which may have a substituent,that is an alkyl group, an alkenyl group, an aryl group, an alkoxygroup, an alkylamino group, an alkylthio group, an acyl group, acarboxyl group and an alkoxycarbonyl group, includes the same one as thesubstituent of the above heterocyclic ring which may have a substituent.

The alkynyl group as the substituent of a heterocyclic ring which mayhave a substituent, may be straight chained, branched or cyclic, andincludes one generally having 2 to 20, preferably 2 to 10 and morepreferably 2 to 6 carbon atoms, wherein not less than one carbon-carbontriple bond is included in the chain of an alkyl group having not lessthan two carbon atoms, among the above alkyl groups, which isspecifically exemplified by an ethenyl group, a 2-propynyl group, a2-pentynyl group, a 2-nonyl-3-butynyl group, a cyclohexyl-3-ynyl group,a 4-octynyl group and 1-methyldecyl-5-ynyl group.

The alkylcarbamoyl group as the substituent of a heterocyclic ring whichmay have a substituent, includes one, wherein one or two of hydrogenatoms of a carbamoyl group is each independently replaced by the abovealkyl group, which is specifically exemplified by a methylcarbamoylgroup, an ethylcarbamoyl group, a n-propylcarbamoyl group, anisopropylcarbamoyl group, a n-butylcarbamoyl group, an isobutylcarbamoylgroup, a tert-butylcarbamoyl group, a pentylcarbamoyl group, ahexylcarbamoyl group, a heptylcarbamoyl group, an octylcarbamoyl group,a nonylcarbamoyl group, a decylcarbamoyl group, a dodecylcarbamoylgroup, a tetradecylcarbamoyl group, a pentadecylcarbamoyl group, ahexadecylcarbamoyl group, a heptadecylcarbamoyl group, anonadecylcarbamoyl group, an icosylcarbamoyl group, acyclopentylcarbamoyl group, a cyclohexylcarbamoyl group, adimethylcarbamoyl group, an ethylmethylcarbamoyl group, adiethylcarbamoyl group, a methylpropylcarbamoyl group, adipropylcarbamoyl group, an ethylhexylcarbamoyl group, adibutylcarbamoyl group, a heptylmethylcarbamoyl group, amethyloctylcarbamoyl group, decylmethylcarbamoyl group,adodecylethylcarbamoyl group, a methylpentadecylcarbamoyl group, anethyloctadecylcarbamoyl group a cyclopentylmethylcarbamoyl group, acyclohexylmethylcarbamoyl group, a cyclohexylethylcarbamoyl group, acyclohexylpropylcarbamoyl group, a cyclohexylbutylcarbamoyl group and adicyclohexylcarbamoyl group.

The compound having a heterocyclic ring in a deuteration method of thepresent invention includes, a heterocyclic ring itself as describedabove, or said heterocyclic ring bound with sugar chain, variouscompounds or polymers, and specific examples of the latter include, forexample, nucleosides such as adenosine, deoxyadenosine, guanosine,thymidine, uridine, inosine, deoxyguanosine, deoxythymidine anddeoxyuridine; and amino acids such as tryptophan.

In a method for deuteration of the present invention, specific examplesof a deuterated solvent used as a heavy hydrogen source to deuterate aheterocyclic ring include, in the case where heavy hydrogen isdeuterium, deuterium oxide (D₂O), deuterated alcohols such as deuteratedmethanol, deuterated ethanol, deuterated isopropanol, deuteratedbutanol, deuterated tert-butanol, deuterated pentanol, deuteratedhexanol, deuterated heptanol, deuterated octanol, deuterated nonanol,deuterated decanol, deuterated undecanol and deuterated dodecanol,deuterated carboxylic acids such as deuterated formic acid, deuteratedacetic acid, deuterated propionic acid, deuterated butyric acid,deuterated isobutyric acid, deuterated valeric acid, deuterateisovaleric acid and deuterated pivalic acid, deuterated ketones such asdeuterated acetone, deuterated methyl ethyl ketone, deuterated methylisobutyl ketone, deuterated diethyl ketone, deuterated dipropyl ketone,deuterated diisopropyl ketone and deuterated dibutyl ketone, organicsolvents such as deuterated dimethylsulfoxide, and among others,deuterium oxide and deuterated alcohols are preferable, and deuteriumoxide and deuterated methanol are more preferable, and deuterium oxideis particularly preferable in view of environmental aspect oroperability. In the case where heavy hydrogen is tritium, specificexamples of a deuterated solvent as a deuteration source include tritiumoxide (T₂O), etc.

The deuterated solvent may be one wherein at least one hydrogen atom ina molecule is deuterated, and for example, deuterated alcohols whereinat least a hydrogen atom in a hydroxyl group is deuterated, ordeuterated carboxylic acids wherein at least a hydrogen atom in acarboxyl group is deuterated, can be used in a method for deuteration ofthe present invention, and among others, a solvent wherein all hydrogenatoms in a molecule are deuterated is particularly preferable.

As an amount of a deuterated solvent to be used is increasing,deuteration of the present invention tends to proceed further, however,in view of cost, the amount of a deuterated solvent is such level, aslower limit, of generally not less than equimolar, preferably in theorder of, not less than 10 molar times, 20 molar times, 30 molar timesand 40 molar times, and as upper limit, generally 250 molar times,preferably 150 molar times, of a heavy hydrogen atom contained in thedeuterated solvent, relative to hydrogen atoms deuteratable in acompound having a heterocyclic ring as a reactive substrate.

Further, in the case where a compound having a heterocyclic ring as areactive substrate of a method for deuteration of the present inventionis solid which hardly dissolves in a deuterated solvent, a reactionsolvent may be used in combination with the deuterated solvent, ifnecessary.

The specific example of the reaction solvent to be used if necessary,includes organic solvents which are not deuterated with heavy hydrogengas, containing ethers such as dimethyl ether, diethyl ether,diisopropyl ether, ethylmethyl ether, tert-butylmethyl ether,1,2-dimethoxyethane, oxirane, 1,4-dioxane, dihydropyrane andtetrahydrofuran; aliphatic hydrocarbons such as hexane, heptane, octane,nonane, decane and cyclohexane; and organic solvents which can be usedas heavy hydrogen source of the present invention even if deuterated byheavy hydrogen gas containing water; alcohols such as methanol, ethanol,isopropanol, butanol, tert-butanol, pentanol, hexanol, heptanol,octanol, nonanol, decanol, undecanol and dodecanol; carboxylic acidssuch as formic acid, acetic acid, propionic acid, butyric acid,isobutyric acid, valeric acid, isovaleric acid and pivalic acid; ketonessuch as acetone, methylethylketone, methylisobutylketone, diethylketone,dipropylketone, diisopropylketone and dibutylketone; anddimethylsulfoxide.

The activated catalyst selected from a palladium catalyst, a platinumcatalyst, a rhodium catalyst, a ruthenium catalyst, a nickel catalystand a cobalt catalyst in the present invention (hereinafter may beabbreviated as an “activated catalyst”) means a so-called palladiumcatalyst, platinum catalyst, rhodium catalyst, ruthenium catalyst,nickel catalyst or cobalt catalyst (hereinafter may be abbreviated as a“non-activated catalyst” or simply as a “catalyst”) which is activatedby contact with hydrogen gas or heavy hydrogen gas.

In a method for deuteration of the present invention, deuteration may becarried out using a catalyst activated in advance, or activation of acatalyst and deuteration of reactive substrate may be simultaneouslycarried out in the co-presence of a non-activated catalyst with hydrogengas or heavy hydrogen gas in a deuteration reaction system.

When deuteration is carried out using a catalyst activated by hydrogengas or heavy hydrogen gas in advance, a part of gas phase in adeuteration reactor may be replaced with an inert gas such as nitrogenand argon. When a substrate of the deuteration reaction is hardlyreduced with hydrogen gas, and the like, a part of gas phase in areactor may be replaced with hydrogen gas or heavy hydrogen gas as wellas with the above inert gas.

When activation of a catalyst and deuteration of a reactive substrateare simultaneously carried out, the reaction may be conducted afterreplacing a part of gas phase in a reactor with hydrogen gas or heavyhydrogen gas or directly passing hydrogen gas or heavy hydrogen gasthrough a reaction solution. Namely, a non-activated catalyst isactivated by hydrogen gas or heavy hydrogen gas present in a deuterationreaction system.

In a method for deuteration of the present invention, a reactor ispreferably in sealed state or nearly sealed state (hereinafter may beabbreviated as “sealed state”) so that the reaction system is, as theresult, in pressurized state. Nearly sealed state involves, for example,a case of so-called continuous reaction where a reaction substrate iscontinuously charged into a reactor and a product is continuously takenout therefrom.

As described above, in a method for deuteration of the presentinvention, temperature of a reaction system can be easily elevated toperform deuteration efficiently, because the reactor is in sealed state.

Further, when activation of a catalyst and deuteration of a reactivesubstrate are simultaneously carried out, a complicated process that acatalyst is activated in advance is not required, and also a complicatedoperation that freeze-pumping is repeated as described in Chem. Commun.,2001,367-368 is not needed.

Furthermore, by using a catalyst activated with hydrogen gas or heavyhydrogen gas in advance for deuteration in sealed state, onlydeuteration of a substrate proceeds without being reduced at all becausehydrogen gas or heavy hydrogen gas is not present in a deuterationreaction system, even the substrate is generally labile to be reducedwith hydrogen gas or the like.

The activated catalyst in the present invention includes a palladiumcatalyst, a platinum catalyst, a rhodium catalyst, a ruthenium catalyst,a nickel catalyst and a cobalt catalyst, as described above, and amongothers, a palladium catalyst, a platinum catalyst and a rhodium catalystis preferable, a palladium catalyst and a platinum catalyst is morepreferable, and a palladium catalyst is particularly preferable. Thesecatalysts can be used effectively by themselves or in combinationaccordingly.

The palladium catalyst includes one having generally 0 to 4, preferably0 to 2 and more preferably 0 valence of a palladium atom.

The platinum catalyst includes one having generally 0 to 4, preferably 0to 2 and more preferably 0 valence of a platinum atom.

The rhodium catalyst includes one having generally 0 or 1, preferably 0valence of a rhodium atom.

The ruthenium catalyst includes one having generally 0 to 2, preferably0 valence of a ruthenium atom.

The nickel catalyst includes one having generally 0 to 2, preferably 0valence of a nickel atom.

The cobalt catalyst includes one having generally 0 or 1, preferably 1valence of a cobalt atom.

The above catalyst may be a metal itself of palladium, platinum,rhodium, ruthenium, nickel or cobalt, oxides, halides or acetates ofthese metals, one which may have a ligand, or may be one consisting ofthese metals, metal oxides, metal halides, metal acetates or metalcomplexes supported on various carriers. Hereinafter, a catalystsupported on a carrier may be abbreviated as a “carrier-supported metalcatalyst”, and a catalyst not supported on a carrier may be abbreviatedas a “metal catalyst”.

Among catalysts in a method for deuteration of the present invention, aligand of a metal catalyst which may have a ligand, includes, forexample, 1,5-cyclooctadiene (COD), dibenzylideneacetone (DBA),bipyridine (BPY), phenanthroline (PHE), benzonitrile (PhCN), isocyanide(RNC), triethylarsine (As(Et)₃), acetylacetonate (acac); organicphosphine ligands such as dimethylphenylphosphine (P(CH₃)₂Ph),diphenylphosphinoferrocene (DPPF), trimethylphosphine (P(CH₃)₃),triethylphosphine (PEt3), tri-tert-butylphosphine (PtBu3),tricyclohexylphosphine (PCy₃), trimethoxyphosphine (P(OCH₃)₃),triethoxyphosphine (P(OEt)₃), tri-tert-butoxyphosphine (P(OtBu)₃),triphenylphosphine (PPh₃), 1,2-bis(diphenylphosphino)ethane (DPPE),triphenoxyphosphine (P(OPh)₃) and o-tolylphosphine (P(o-tolyl)₃).

Specific examples of the palladium based metal catalyst include, forexample, Pd; palladium hydroxide catalysts such as Pd(OH)₂; palladiumoxide catalysts such as PdO; halogenated palladium catalysts such asPdBr2, PdCl₂ and PdI₂; palladium acetate catalysts such as palladiumacetate (Pd(OAc)₂) and palladium trifluoroacetate (Pd(OCOCF₃)₂);palladium metal complex catalysts which are coordinated with a ligandsuch as Pd(RNC)₂Cl₂, Pd(acac)₂,diacetate-bis-(triphenylphosphine)palladium [Pd(OAc)₂(PPh₃)₂],Pd(PPh₃)₄, Pd₂(dba)₃, Pd(NH₃)₂Cl₂, Pd(CH₃CN)₂Cl₂,dichlorobis(benzonitrile)palladium [Pd(PhCN)₂Cl₂], Pd(dppe)Cl₂,Pd(dppf)Cl₂, Pd(PCy₃)₂Cl₂, Pd(PPh₃)₂Cl₂, Pd[P(o-tolyl)₃]₂Cl₂,Pd(cod)₂Cl₂ and Pd(PPh₃)(CH₃CN)₂Cl₂.

Specific examples of the platinum based metal catalyst include, forexample, Pt; platinum oxide catalysts such as PtO₂; halogenated platinumcatalysts such as PtCl₄, PtCl₂ and K₂PtCl₄; platinum metal complexcatalysts which are coordinated with a ligand such as PtCl₂(cod),PtCl₂(dba), PtCl₂(PCy₃)₂, PtCl₂(P(OEt)₃)₂, PtCl₂(P(OtBu)₃)₂, PtCl₂(bpy),PtCl₂(phe), Pt(PPh₃)₄, Pt(cod)₂, Pt(dba)₂, Pt(bpy)₂ and Pt(phe)₂.

Specific examples of the rhodium based metal catalyst include, forexample, Rh and rhodium metal complex catalysts which are coordinatedwith a ligand such as RhCl(PPh₃)₃.

Specific examples of the ruthenium based metal catalyst include, forexample, Ru and ruthenium metal complex catalysts which are coordinatedwith a ligand such as RuCl₂(PPh₃)₃.

Specific examples of the nickel based metal catalyst include, forexample, Ni; nickel oxide catalysts such as NiO; halogenated nickelcatalysts such as NiCl₂; nickel metal complex catalysts which arecoordinated with a ligand such as NiCl₂(dppe), NiCl₂(PPh₃)₂, Ni(PPh₃)₄,Ni(P(OPh)₃)₄ and Ni(cod)₂.

Specific examples of the cobalt based metal catalyst include, forexample, cobalt metal complex catalysts which are coordinated with aligand such as Co(C₃H₅){P(OCH₃)₃}₃.

A carrier, in the case where the above catalyst is supported on acarrier, includes, for example, carbon, alumina, silica gel, zeolite,molecular sieve, ion-exchange resins and polymers, and among others,carbon is preferable.

The ion exchange resin used as a carrier may be one having no adverseeffect on deuteration of the present invention, and includes, forexample, a cation exchange resin and an anion exchange resin.

The cation exchange resin includes, for example, a weak acidic cationexchange resin and strong acidic cation exchange resin. The anionexchange resin includes, for example, a weak basic anion exchange resinand a strong basic anion exchange resin.

The ion exchange resin generally contains a polymer cross-linked with abifunctional monomer as a skeleton polymer, to which an acidic group ora basic group is bonded and then is exchanged by various cations andanions (a counter ion), respectively.

Specific examples of the weak acidic cation exchange resin include, forexample, one obtained by hydrolysis of a polymer of acrylate ester or amethacrylate ester, cross-linked by divinylbenzene.

Specific examples of the strong acidic cation exchange resin include,for example, one obtained by sulfonation of a copolymer ofstyrene-divinylbenzene.

Specific examples of the strong basic anion exchange resin include, forexample, one wherein an amino group is bonded to an aromatic ring of acopolymer of stylene-divinylbenzene.

Strength of basicity of a basic anion exchange resin increases with anamino group bonded in the order of a primary amino group, a secondaryamino group, a tertiary amino group and a quaternary ammonium salt.

The ion exchange resin generally available on the market may be used aswell as the above ion exchange resin.

The polymer used as a carrier is not especially limited unless it hasserious effects on deuteration of the present invention, however, anexample of such a polymer includes, for example, one obtained bypolymerization or copolymerization of a monomer shown by the followinggeneral formula [1]:

(wherein R¹ is a hydrogen atom, a lower alkyl group, a carboxyl group, acarboxyalkyl group, an alkoxycarbonyl group, a hydroxyalkoxycarbonylgroup, a cyano group or a formyl group; R² is a hydrogen atom, a loweralkyl group, a carboxyl group, an alkoxycarbonyl group, ahydroxyalkoxycarbonyl group, a cyano group or a halogen atom; R³ is ahydrogen atom, a lower alkyl group, a haloalkyl group, a hydroxyl group,an aryl group which may have a substituent, an aliphaticheterocyclic,group an aromatic heterocyclic group, a halogen atom, analkoxycarbonyl group, a hydroxyalkoxycarbonyl group, a sulfo group, acyano group, a cyano-containing alkyl group, an acyloxy group, acarboxyl group, a carboxyalkyl group, an aldehyde group, an amino group,an aminoalkyl group, a carbamoyl group, a N-alkylcarbamoyl group or ahydroxyalkyl group, and R¹ and R² may form an alicyclic ring togetherwith the adjacent —C═C— bond).

In the general formula [1], the lower alkyl group shown by R¹ to R³ maybe straight chained, branched or cyclic, and includes an alkyl grouphaving 1 to 6 carbon atoms, which is specifically exemplified by amethyl group, an ethyl group, a n-propyl group, an isopropyl group, an-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group,a n-pentyl group, an isopentyl group, a tert-pentyl group, a1-methylpentyl group, a n-hexyl group, an isohexyl group, a cyclopropylgroup, a cyclopentyl group and a cyclohexyl group.

The carboxyalkyl group shown by R¹ and R² includes one, wherein a partof hydrogen atoms of the above lower alkyl group is replaced by acarboxyl group, which is specifically exemplified by a carboxymethylgroup, a carboxyethyl group, a carboxypropyl group, a carboxybutylgroup, a carboxypentyl group and a carboxyhexyl group.

The alkoxycarbonyl group shown by R¹ to R³ includes preferably onehaving 2 to 11 carbon atoms, which is specifically exemplified by amethoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group,a butoxycarbonyl group, a pentyloxycarbonyl group, a hexyloxycarbonylgroup, a heptyloxycarbonyl group, a 2-ethylhexyloxycarbonyl group, anoctyloxycarbonyl group, a nonyloxycarbonyl group and a decyloxycarbonylgroup.

The hydroxyalkoxycarbonyl group shown by R¹ to R³ includes one, whereina part of hydrogen atoms of the above alkoxycarbonyl group having 2 to11 carbon atoms is replaced by a hydroxyl group, which is specificallyexemplified by a hydroxymethyloxycarbonyl group, ahydroxyethyloxycarbonyl group, a hydroxypropyloxycarbonyl group, ahydroxybutyloxycarbonyl group, a hydroxypentyloxycarbonyl group, ahydroxyhexyloxycarbonyl group, a hydroxyheptyloxycarbonyl group, ahydroxyoctyloxycarbonyl group, a hydroxynonyloxycarbonyl group and ahydroxydecyloxycarbonyl group.

The halogen atom shown by R² and R³ includes, for example, fluorine,chlorine, bromine and iodine.

The haloalkyl group shown by R³ includes one having 1 to 6 carbon atoms,wherein the above lower alkyl group shown by R¹ to R³ is halogenated(for example, fluorinated, chlorinated, brominated and iodiriated),which is specifically exemplified by a chloromethyl group, a bromomethylgroup, a trifluoromethyl group, a 2-chloroethyl group, a 3-chloropropylgroup, a 3-bromopropyl group, a 3,3,3-trifluoropropyl group, a4-chlorobutyl group, a 5-chloropentyl group and a 6-chlorohexyl group.

The aryl group of the aryl group which may have a substituent includes,for example, a phenyl group, a tolyl group, a xylyl group and a naphthylgroup, and said substituent includes, for example, an amino group, ahydroxyl group, a lower alkoxy group and a carboxyl group. Specificexamples of the substituted aryl group include, for example, anaminophenyl group, a toluidino group, a hydroxyphenyl group, amethoxyphenyl group, a tert-butoxyphenyl group and a carboxyphenylgroup.

The aliphatic heterocyclic group includes preferably a 5- or 6-memberedone having 1 to 3 hetero atoms such as a nitrogen atom, an oxygen atomand a sulfur atom, which is specifically exemplified by a2-oxopyrrolidyl group, a piperidyl group, a piperidino group, apiperazinyl group and a morpholino group.

The aromatic heterocyclic group includes preferably a 5- or 6-memberedone having 1 to 3 hetero atoms such as a nitrogen atom, an oxygen atomand a sulfur atom, which is specifically exemplified by a pyridyl group,an imidazolyl group, a thiazolyl group, a furyl group and a pyranylgroup.

The cyano-containing alkyl group includes one, wherein a part ofhydrogen atoms of the above lower alkyl group is replaced by a cyanogroup, which is specifically exemplified by a cyanomethyl group, a2-cyanoethyl group, a 2-cyanopropyl group, a 3-cyanopropyl group, a2-cyanobutyl group, a 4-cyanobutyl group, a 5-cyanopentyl group and a6-cyanohexyl group.

The acyloxy group includes one derived from a carboxylic acid having 2to 20 carbon atoms, which is specifically exemplified by an acetyloxygroup, a propionyloxy group, a butyryloxy group, a pentanoyloxy group, anonanoyloxy group, a decanoyloxy group and a benzoyloxy group.

The aminoalkyl group includes one, wherein a part of hydrogen atoms ofthe above lower alkyl group is replaced by an amino group, which isspecifically exemplified by an aminoethyl group, an aminoethyl group, anaminopropyl group, an aminobutyl group, an aminopentyl group and anaminohexyl group.

The N-alkylcarbamoyl group includes one, wherein a part of hydrogenatoms of a carbamoyl group is replaced by an alkyl group, which isspecifically exemplified by an N-methylcarbamoyl group, anN-ethylcarbamoyl group, an N-n-propylcarbamoyl group, anN-isopropylcarbamoyl group, an N-n-butylcarbamoyl group and anN-tert-butylcarbamoyl group.

The hydroxyalkyl group includes one, wherein a part of hydrogen atoms ofthe above lower alkyl group is replaced by a hydroxyl group, which isspecifically exemplified by a hydroxymethyl group, a hydroxyethyl group,a hydroxypropyl group, a hydroxybutyl group, a hydroxypentyl group and ahydroxyhexyl group.

The aliphatic ring in the case where R¹ and R² are bonded together withthe adjacent —C═C— bond to form an alicyclic ring, includes anunsaturated alicyclic ring having 5 to 10 carbon atoms, and may bemonocyclic or polycyclic, which is specifically exemplified by anorbornene ring, a cyclopentene ring, a cyclohexene ring, a cyclooctenering and a cyclodecene ring.

The specific examples of the monomer shown by the general formula [1]include ethylenically unsaturated aliphatic hydrocarbons having 2 to 20carbon atoms such as ethylene, propylene, butylene and isobutylene;ethylenically unsaturated aromatic hydrocarbons having 8 to 20 carbonatoms such as styrene, 4-methylstyrene, 4-ethylstyrene anddivinylbenzene; alkenyl esters having 3 to 20 carbon atoms such as vinylformate, vinyl acetate, vinyl propionate and isopropenyl acetate;halogen-containing ethylenically unsaturated compounds having 2 to 20carbon atoms such as vinyl chloride, vinylidene chloride, vinylidenefluoride and tetrafluoroethylene; ethylenically unsaturated carboxylicacids having 3 to 20 carbon atoms such as acrylic acid, methacrylicacid, itaconic acid, maleic acid, fumaric acid, crotonic acid,vinylacetic acid, allylacetic acid and vinylbenzoic acid (these acidsmay form an alkali metal salt such as sodium and potassium, or anammonium salt); ethylenically unsaturated carboxylic acid esters such asmethyl methacrylate, ethyl methacrylate, propyl methacrylate, butylmethacrylate, 2-ethylhexyl methacrylate, methyl acrylate, ethylacrylate, propyl acrylate, butyl acrylate, 2-ethylhexyl acrylate, laurylmethacrylate, stearyl acrylate, methyl itaconate, ethyl itaconate,methyl maleate, ethyl maleate, methyl fumarate, ethyl fumarate, methylcrotonate, ethyl crotonate and methyl 3-butenoate; cyano-containingethylenically unsaturated compounds having 3 to 20 carbon atoms such asacrylonitrile, methacrylonitrile and allyl cyanide; ethylenicallyunsaturated amide compounds having 3 to 20 carbon atoms such asacrylamide and methacrylamide; ethylenically unsaturated aldehydeshaving 3 to 20 carbon atoms such as acrolein and crotonaldehyde;ethylenically unsaturated sulfonic acids having 2 to 20 carbon atomssuch as vinylsulfonic acid and 4-vinylbenzene sulfonic acid (these acidsmay form an alkali metal salts such as sodium and potassium);ethylenically unsaturated aliphatic amines having 2 to 20 carbon atomssuch as vinylamine and allylamine; ethylenic unsaturated aromatic amineshaving 8 to 20 carbon atoms such as vinylaniline; ethylenicallyunsaturated aliphatic heterocyclic amines having 5 to 20 carbon atomssuch as N-vinylpyrrolidone and vinylpiperidine; ethylenicallyunsaturated alcohols having 3 to 20 carbon atoms such as allyl alcoholand crotyl alcohol; ethylenically unsaturated phenols having 8 to 20carbon atoms such as 4-vinylphenol, etc.

When the above polymer, and the like is used as a carrier, use of thecarrier that is hardly deuterated itself by deuteration of the presentinvention is preferable, however, a catalyst supported on the carrierdeuteratable itself can also be used for deuteration of the presentinvention.

In a method for deuteration of the present invention, among the abovecarrier-supported metal catalysts, a palladium carbon, a palladiumhydroxide carbon or a platinum carbon are preferably used. Among others,a palladium carbon and a palladium hydroxide carbon are easy inindustrial operability and have superior catalytic activity, and inparticular, use of a palladium carbon mostly provides further efficientdeuteration reaction.

In the carrier-supported catalyst, content of the catalyst metal whichis palladium, platinum, rhodium, ruthenium, nickel and cobalt, isgenerally 1 to 99% by weight, preferably 1 to 50% by weight, morepreferably 1 to 30% by weight, further more preferably 1 to 20% byweight, and particularly preferably 5 to 10% by weight based on wholecatalyst.

In a method for deuteration of the present invention, amount of theactivated catalyst or non-activated catalyst to be used is generallyso-called catalyst quantity, preferably in the order of, 0.01 to 200% byweight, 0.01 to 100% by weight, 0.01 to 50% by weight, 0.01 to 20% byweight, 0.1 to 20% by weight, 1 to 20% by weight and 10 to 20% byweight, relative to a compound having a heterocyclic ring to be used asa reactive substrate, irrespective of whether the catalyst is supportedby a carrier or not, and upper limit content of the catalyst metal insaid whole catalyst is preferably in the order of, 20% by weight, 10% byweight, 5% by weight and 2% by weight, while lower limit thereof ispreferably in the order of, 0.0005% by weight, 0.005% by weight, 0.05%by weight and 0.5% by weight.

When a compound having a heterocyclic ring is deuterated, 2 or morekinds of various catalysts as described above can be used in anappropriate combination.

In the case where 2 or more kinds of catalysts are used in combination,amount of the catalysts to be used may be set so that total amount ofthe catalysts becomes the amount of the catalyst to be used as describedabove.

In the case when a non-activated catalyst is used in a reaction of thepresent invention, amount of hydrogen to be used when hydrogen gas ispresent in a reaction system to activate the non-activated catalyst maybe a little more than necessary amount to activate the catalyst toefficiently carry out activation of the catalyst, though there ispossibility that excessive amount of hydrogen shows adverse effect on adeuteration reaction of the present invention such as hydrogenation of adeuterated solvent as heavy hydrogen source. Such amount of hydrogen gasis generally 1 to 20,000 equivalents and preferably 10 to 700equivalents, relative to the catalyst.

Amount of heavy hydrogen to be used when heavy hydrogen is present in areaction system to activate the non-activated catalyst may be necessaryamount to activate the catalyst, generally 1 to 20,000 equivalents andpreferably 10 to 700 equivalents, relative to the catalyst, however,even if amount of said heavy hydrogen is excessively large, deuterationof the present invention can be performed without any problem, becausesaid heavy hydrogen is in contact with a deuterated solvent in areaction system and has effect to further deuterate said solvent.

In a method for deuteration of the present invention, reactiontemperature may be determined so that a reaction system is in refluxingstate at temperature higher than boiling point (at atmospheric pressure)of the solvent, and lower limit of such reaction temperature ispreferably in the order of, +3° C., +5° C., +10° C. and +20° C.exceeding boiling point of the solvent, and upper limit thereof ispreferably in the order of, +100° C., +80° C., +70° C. and +60° C.exceeding boiling point of the solvent.

Setting of the above reaction temperature in a reactor in sealed statemay be performed by heating and/or pressurizing, thereby to make insideof the reaction system in pressurized state.

Pressurization of a reaction system may be performed using hydrogen gasto activate a catalyst, or may be performed using further inert gas suchas nitrogen gas and argon gas.

Reaction time in a method for deuteration of the present invention isgenerally 30 minutes to 100 hours, preferably 1 to 50 hours, morepreferably 1 to 30 hours and further more preferably 3 to 30 hours.

A method for deuteration of the present invention will be specificallyexplained by taking, as an example, the case of using heavy water asheavy hydrogen source and using a palladium catalyst as a non-activatedcatalyst.

For example, a compound having a heterocyclic ring (substrate) and apalladium catalyst are added to a deuterated solvent, followed bysealing the reaction system, replacing atmosphere in the reaction systemwith hydrogen gas and reacting with stirring in an oil bath at about 103to 200° C. for about 30 minutes to 100 hours. After completion of thereaction, when the reaction product is soluble in a deuterated solvent,the catalyst is filtered off from the reaction solution, and thefiltrate is subjected to, as it is, structural analysis by ¹H-NMR,²H-NMR and mass spectrum measurements. When the reaction product ishardly soluble in the deuterated solvent, the reaction product isisolated from the reaction solution to be subjected to structuralanalysis by ¹H-NMR, ²H-NMR and mass spectrum measurements.

When the product is hardly soluble in a deuterated solvent, theisolation of the product from the reaction solution may be carried outaccording to known purification methods such as extraction of theproduct from the reaction solution using an organic solvent in which theproduct is soluble and then filtering off the catalyst.

Even when a compound having a heterocyclic ring contains a halogen atomas a substituent, only the heterocyclic ring can be deuterated withoutthe above halogen atom being substituted by a hydrogen atom or adeuterium atom, or even when the compound having a heterocyclic ringcontains a substituent such as a nitro group and a cyano group, only theheterocyclic ring can be deuterated without the above substituent beingreduced, by performing a method for deuteration of the present inventionusing a catalyst activated in advance as an activated catalyst and adeuterated solvent as heavy hydrogen source.

As described above, in accordance with a method for deuteration of thepresent invention which comprises subjecting a compound having aheterocyclic ring to sealed refluxing state in a deuterated solvent inthe presence of an activated catalyst, a hydrogen atom belonging to theheterocyclic ring of a compound having a heterocyclic ring can bedeuterated very efficiently because deuteration reaction temperature canbe maintained at higher than boiling point of the solvent.

Further, in accordance with a method for deuteration of the presentinvention, not only a hydrogen atom belonging to a heterocyclic ring,but also a hydrogen atom belonging to a carbon atom present in asubstituent of a heterocyclic ring (for example, one derived from analkyl group, an alkenyl group, an aralkyl group, an alkoxy group, analkylthio group, an alkylsulfonyl group, an alkylsulfinyl group, analkylphosphino group, an alkylphosphinoyl group, an alkylamino group, analkoxycarbonyl group, an alkoxysulfonyl group and an acyl group) or ahydrogen atom bound to a carbon atom present in a sugar chain, variouscompounds or polymers, bound to a heterocyclic ring can also bedeuterated.

In the following, the present invention is explained in further detailreferring to Examples, but the present invention is not limited theretoby any means.

Further, in the following Examples, isolation yield means yield of acompound isolated after completion of the reaction irrespective ofwhether deuterated or not, and deuteration ratio means ratio of amountof deuterated atoms to amount of deuteratable hydrogen atoms in acompound isolated after completion of the reaction. In the followingExamples, deuteration ratio of a hydrogen atom in each position of anisolated compound is shown.

EXAMPLE Example 1

In 17 mL of deuterium oxide (D₂O) were suspended 500 mg of imidazol and50 mg of palladium carbon (Pd 10%), followed by replacing atmosphere ofa sealed reaction system with hydrogen gas and conducting a reaction inan oil bath at 160° C. for about 24 hours. After completion of thereaction, the reaction solution was extracted with ether, followed byfiltering out the catalyst and concentration of the filtrate underreduced pressure to obtain 500 mg of deuterated compound (isolationyield 95%). Structural analysis of thus obtained compound by ¹H-NMR,²H-NMR and mass spectrum measurements gave the following deuterationratios for each hydrogen atom of the compound obtained. Deuterationratio to total hydrogen atoms in the position (1) shown by the followingformula was 99%, and deuteration ratio to total hydrogen atoms in theposition (2) was also 99%.

Examples 2 to 5

Similar deuteration reactions as in Example 1 were conducted except forusing substrates shown in the following Table 1. Isolation yields anddeuteration ratios of each deuterated compound are shown in Table 1.Hereinafter, deute ration ratios in each Example were calculated in thesame manner as in Example 1.

TABLE 1 Isolation Deuteration Reactive substrate Product yield (%) ratio(%) Example 2

99 (1) 99(2) 99 Example 3

86 (1) 99(2) 91(3) 79 Example 4

92 (1) 98(2) 94 Example 5

72 (1) 99(2) 99(3) 99

Examples 6 to 7

Similar deuteration reactions as in Example 1 were conducted except forusing adenine as a substrate and conducting the reactions under reactionconditions shown in the following Table 2. Isolation yields anddeuteration ratios of the obtained compounds are shown together in Table2.

TABLE 2

Reaction Reaction Isolation Deuteration temperature time yield (%) ratio(%) Example 6 110° C. 24 hours 94 48 Example 7 140° C. 48 hours 36 95

Deuteration ratio in Table 2 is ratio of amount of total deuteratedatoms to amount of total deuteratable hydrogen atoms in the positions of(1) and (2) in the above chemical formula.

Examples 8 to 9

Similar deuteration reactions as in Example 1 were conducted except forusing adenosine as a substrate and carrying out the reactions underreaction conditions shown in the following Table 3. Isolation yields anddeuteration ratios of the obtained compounds are shown together in Table3.

TABLE 3

Reaction Reaction Isolation Deuteration temperature time yield (%) ratio(%) Example 8 110° C. 48 hours 99 (1) 94, (2) 92 Example 9 140° C. 48hours 74 (1) 91, (2) 91

Examples 10 to 12

Similar deuteration reactions as in Example 1 were conducted except forusing guanosine as a substrate and carrying out the reactions underreaction conditions shown in the following Table 4. Isolation yields anddeuteration ratios of the obtained compounds are shown together in Table4.

TABLE 4

Reaction Reaction Isolation Deuteration temperature time yield (%) ratio(%) Example 10 110° C. 48 hours 94 (1) 94 Example 11 140° C. 48 hours 99(1) 93 Example 12 160° C. 24 hours 98 (1) 96

Examples 13 to 14

Similar deuteration reactions as in Example 1 were conducted except forusing thymine as a substrate and carrying out the reactions underreaction conditions shown in the following Table 5. Isolation yields anddeuteration ratios of the obtained compounds are shown together in Table5.

TABLE 5

Reaction Reaction Isolation Deuteration temperature time yield (%) ratio(%) Example 13 110° C. 24 hours 96 (1) 99, (2) 64 Example 14 140° C. 48hours 65 (1) 96, (2) 94

Example 15

Similar deuteration reaction as in Example 1 was conducted except forusing cytosine as a substrate and carrying out the reaction at 160° C.for 48 hours. Isolation yield of the obtained compound was 98% anddeuteration ratios thereof were (1) 96% and (2) 96%.

Example 16

Similar deuteration reaction as in Example 1 was conducted except forusing uracil as a substrate and carrying out the reaction at 160° C. for48 hours. Isolation yield of the obtained compound was 94% anddeuteration ratios thereof were (1) 98% and (2) 93%.

Example 17

Similar deuteration reaction as in Example 1 was conducted except forusing uridine as a substrate and carrying out the reaction at 160° C.for 24 hours in a sealed state. Isolation yield of the obtained compoundwas 85% and deuteration ratios thereof were (1) 48% and (2) 95%.

Examples 18 to 19

Similar deuteration reactions as in Example 1 were conducted except forusing inosine as a substrate and carrying out the reactions underreaction conditions shown in the following Table 6. Isolation yields anddeuteration ratios of the obtained compounds are shown together in Table6.

TABLE 6

Reaction Reaction Isolation Deuteration temperature time yield (%) ratio(%) Example 18 110° C. 48 hours 98 (1) 79, (2) 84 Example 19 140° C. 48hours 90 (1) 85, (2) 97

Example 20

Similar deuteration reaction as in Example 1 was conducted except forusing hypoxanthine as a substrate and carrying out the reaction at 110°C. for 48 hours. Isolation yield of the obtained compound was 62% anddeuteration ratio thereof to total deuteratable hydrogen atoms in thepositions (1) and (2) was 95%.

Examples 21 to 22

Similar deuteration reactions as in Example 1 were conducted except forusing 3-methylindole as a substrate and carrying out the reactions underreaction conditions shown in the following Table 7. Isolation yields anddeuteration ratios of the obtained compounds are shown together in Table7.

TABLE 7

Reaction Reaction Isolation Deuteration temperature time yield (%) ratio(%) Example 110° C. 24 hours 50 (2) + (5) 44, (8) 97, 21 (4) 0, (6) 0,(7) 97 Example 140° C. 48 hours 82 (2) + (5) 53, (8) 92, 22 (4) 28, (6)20, (7) 81

Deuteration ratio of (2)+(5) in Table 7 means a deuteration ratio tototal deuteratable hydrogen atoms in the positions of (2) and (5).

Example 23

Similar deuteration reaction as in Example 1 was conducted except forusing 5-methylindole as a substrate and carrying out the reaction at140° C. for 48 hours. Isolation yield of the obtained compound was 65%and deuteration ratios thereof were (2) 100%, (3) 90%, (4) 27%, (5) 95%,(6) 99% and (7) 38%.

Example 24

Similar deuteration reaction as in Example 1 was conducted except forusing 7-methylindole as a substrate and carrying out the reaction at140° C. for 48 hours. Isolation yield of the obtained compound was 79%and deuteration ratios thereof were (2) 96%, (3) 95%, (4) 95%, (5)+(6)59% and (7) 96%.

Example 25

Similar deuteration reaction as in Example 1 was conducted except forusing 3,5-dimethylpyrazole as a substrate and carrying out the reactionat 140° C. for 48 hours. Isolation yield of the obtained compound was55% and deuteration ratios thereof were (3)+(5) 96% and (4) 95%.

Example 26

Similar deuteration reaction as in Example 1 was conducted except forusing 5-methylbenzimidazole as a substrate and carrying out the reactionat 140° C. for 48 hours. Isolation yield of the obtained compound was99% and deuteration ratios thereof were (2) 98%, (4) 98%, (5) 95%, (6)19% and (7) 98%.

Example 27

Similar deuteration reaction as in Example 1 was conducted except forusing 7-azaindole as a substrate and carrying out the reaction at 140°C. for 48 hours. Isolation yield of the obtained compound was 92% anddeuteration ratios thereof were (2) 95%, (3) 94%, (4) 94%, (5) 69% and(6) 96%.

Example 28

Similar deuteration reaction as in Example 1 was conducted except forusing L-tryptophan as a substrate and carrying out the reaction at 160°C. for 48 hours. Isolation yield of the obtained compound was 93% anddeuteration ratios thereof were (1) 45%, (2) 47%, (3)+(4) 22% and (5)0%.

Example 29

Similar deuteration reaction as in Example 1 was conducted except forusing 2,3-rutidine as a substrate and carrying out the reaction at 160°C. for 6 hours. Isolation yield of the obtained compound was 74% anddeuteration ratio to total deuteratable hydrogen atoms in the positions(1) to (5) was 98%.

Example 30

Similar deuteration reaction as in Example 1 was conducted except forusing 2-methylimidazole as a substrate and carrying out the reaction at120° C. for 24 hours. Isolation yield of the obtained compound was 99%and deuteration ratios thereof were (1) 99% and (2) 20%.

Example 31

Similar deuteration reaction as in Example 30 was conducted except forusing heavy methanol instead of heavy water. Isolation yield of theobtained compound was 88% and deuteration ratios thereof were (1) 86%and (2) 9%.

As obvious from the results of Examples 30 and 31, a deuterated organicsolvent can also be used as well as heavy water in a method fordeuteration of the present invention.

Example 32

Similar deuteration reaction as in Example 1 was conducted except forusing 2-methylimidazole as a substrate and a platinum carbon (Pt 5%)instead of a palladium carbon. Isolation yield of the obtained compoundwas 95% and deuteration ratios thereof were (1) 93% and (2) 67%.

INDUSTRIAL APPLICABILITY

In accordance with a method for deuteration of the present invention,which comprises subjecting a compound having a heterocyclic ring tosealed refluxing state in a deuterated solvent in the presence of anactivated catalyst, a hydrogen atom belonging to the heterocyclic ringof the compound having a heterocyclic ring can be very easily deuteratedbecause temperature of deuteration reaction can be maintained at notlower than boiling point of the solvent.

Further, a method for deuteration of the present invention can beapplied widely to deuteration of various compounds having a heterocyclicring which are liable to decomposition under supercritical conditions oracidic conditions, leading to industrial and efficient deuteration of acompound having a heterocyclic ring.

1. A method for deuteration of a heterocyclic ring, which comprisessubjecting a compound having a heterocyclic ring to a sealed refluxingstate in a deuterated solvent in the presence of an activated palladiumcatalyst.
 2. The method for deuteration according to claim 1, whereinthe activated palladium catalyst is an activated palladium carbon. 3.The method for deuteration according to claim 1, wherein the activatedpalladium catalyst is one activated with hydrogen gas or heavy hydrogengas present in a deuteration reaction system.
 4. The method fordeuteration according to claim 1, wherein the deuterated solvent isheavy water (D₂O).
 5. The method for deuteration according to claim 1,wherein the heterocyclic ring of the compound having a heterocyclic ringis a 3 to 20 membered ring.